This is a phase I proposal to determine the feasibility of developing newly discovered fluorinated sulfamoylbenzamide (FSBA) derivatives as therapeutic agents for the treatment of chronic hepatitis B virus (HBV) infection. These molecules have been identified as inhibitors of HBV pregenomic (pg) RNA encapsidation, which is essential for the subsequent viral DNA synthesis. Distinct from the mechanism of the currently FDA-approved antiviral nucleos(t)ide analogues that inhibit HBV DNA polymerase, pgRNA assembly into nucleocapsid represents a novel therapeutic target and the FSBA compounds should thus complement the current antiviral medications. Through an extensive structure-activity-relationship (SAR) study, we have now obtained FSBA compounds with nanomolar antiviral activity. In this Phase I project, we propose to advance lead FSBA compounds with the most favorable ADME, safety and pharmacokinetics (PK) profiles for antiviral efficacy study in the HBV transgenic mouse model in vivo. Having confirmed the in vivo antiviral efficacy in the transgenic mice model, we will further evaluate the safety profile and antiviral efficacy of the lead FSBAs in HBV infected human chimeric uPA-SCID mice model in Phase II study. At the end of Phase II, we will advance one lead candidate for extensive IND enabling studies, and prepare a case for human clinical trial.